Rewarming Injury after Cold Preservation

Abstract

Organ dysfunction pertinent to tissue injury related to ischemic ex vivo preservation during transport from donor to recipient still represents a pivotal impediment in transplantation medicine. Cold storage under anoxic conditions minimizes metabolic activity, but eventually cannot prevent energetic depletion and impairment of cellular signal homeostasis. Reoxygenation of anoxically injured tissue may trigger additional damage to the graft, e.g., by abundant production of oxygen free radicals upon abrupt reactivation of a not yet equilibrated cellular metabolism. Paradoxically, this process is driven by the sudden restoration of normothermic conditions upon reperfusion and substantially less pronounced during re-oxygenation in the cold. The massive energy demand associated with normothermia is not met by the cellular systems that still suffer from hypothermic torpor and dys-equilibrated metabolites and eventually leads to mitochondrial damage, induction of apoptosis and inflammatory responses. This rewarming injury is partly alleviated by preceding supply of oxygen already in the cold but more effectively counteracted by an ensuing controlled and slow oxygenated warming up of the organ prior to implantation. A gentle restitution of metabolic turnover rates in line with the resumption of enzyme kinetics and molecular homeostasis improves post transplantation graft function and survival.

First-in-man controlled rewarming and normothermic perfusion with cell-free solution of a kidney prior to transplantation

“…2 However, experimental data indicate that the benefit of ex vivo normothermic perfusion decreases in proportion to the duration of preceding hypothermic storage. 3 This phenomenon seems to be, at least in part, pertinent to a temperature paradox inherent to an abrupt rewarming of previously cold-adapted tissue 4…”

Transient hyperthermia during oxygenated rewarming of isolated rat livers

“…Moreover, large parts of ischemia‐related disorders that occur during hypothermic preservation do not constitute irreversible cell injury. Primarily the re‐establishment of normal metabolism in the dyshomeostatic tissue at the onset of reperfusion triggers the occurrence of functional deficits eventually culminating in structural damage .…”

“…A more modern approach is constituted by normothermic machine perfusion (NMP) providing perfusion under physiological conditions, thereby enabling therapeutic interventions . However, abrupt temperature shifts, that appear when the cold‐stored organ is transferred to normothermic perfusion, were found to negatively impact organ quality . In order to combine favorable transport logistic of simple cold storage and the advantage of organ reconditioning by NMP prior to reperfusion, controlled oxygenated rewarming (COR) was introduced to circumvent dramatic shifts in temperature and to enable a mild adaption of metabolic activity in the vulnerable cold‐stored tissue .…”

In Vitro/Ex Vivo Models for the Study of Ischemia Reperfusion Injury during Kidney Perfusion

“…COR reduces ROS production, improves mitochondrial and aerobic efficiency, enhances kidney function compared to NMP, and improves post-transplant graft outcome compared to CS [31]. As clinical feasibility is demonstrated [32], COR appears to be an alternative post CS compared to NMP [29,33].…”

“…Controlled oxygenated rewarming (COR) represents a brief and controlled return to 20 • C after standard CS. It provides a gradual adaptation of energy metabolism, counteracting rewarming injury [29], and is more protective than oxygenated HMP post-CS or continuous oxygenated HMP [30]. COR reduces ROS production, improves mitochondrial and aerobic efficiency, enhances kidney function compared to NMP, and improves post-transplant graft outcome compared to CS [31].…”